Sarepta’s Pioneering Therapy is Dosed in PrecisionSarepta’s Pioneering Therapy is Dosed in Precision

Sarepta’s Elevidys gene therapy gives families new hope for slowing or halting a rare degenerative disease in kids: Duchenne muscular dystrophy (DMD).

In June 2023, Elevidys was approved by the Food and Drug Administration for treatment of DMD in ambulatory patients aged 4-5 years.

Then in June 2024, the approval was expanded to include all patients aged 4 and older in the US.

Duchenne is a degenerative muscle-wasting disease (read more about DMD at the bottom of this article). Over time, muscle breaks down and children with DMD lose the ability to walk, run, and climb stairs. They are often wheelchair-bound by age 12 and don’t typically live beyond their mid-20s or early 30s, as lung function and cardiac function are lost.

Elevidys cannot restore lost functions; but by slowing or stopping the progression of DMD, it can help maintain a child’s existing mobility. Treatment could preserve the ability to walk longer, maintain upper limb strength in those who have lost ambulation, and further delay progression to other milestones, such as using a ventilator.

Hear five-year-old Gideon Griffiths’ story in this video:

The packaging for Elevidys prioritizes simplicity of design to make it easy for healthcare professionals to accurately prepare and administer the gene therapy for infusion. Primary packaging is a typical vial holding a liquid, plugged with a rubber stopper, and sealed with a plastic cap.

Sarepta worked with global brand design agency Marks to create unique secondary package format that accommodates up to 61 variants.

Why so many variations? The Elevidys dose is calculated based on the patient’s body weight. The recommended dose is 1.33 x 10¹⁴ vg (vector genomes) per kilogram of body weight.

So the number of vials in a patient’s custom package can be anywhere from 10 to 70, with each vial containing an extractable volume of 10 mL of Elevidys, along with excipients (specifically 200mM sodium chloride, 13 mM tromethamine HCl, 7mM tromethamine, 1mM magnesium chloride, 0.001% poloxamer 188).

Elevidys is a gene therapy, not a drug, given by infusion in a hospital. The one-time intravenous infusion typically takes 1.5 to 2 hours, depending, again, on the patient’s weight.

The secondary packaging design for Elevidys underwent several iterations during development, with input from various stakeholders, including Sarepta, children’s hospitals, and contract manufacturing organizations (CMOs), to ensure it met all requirements for safety, packing, storage, and ease of use.

Regarding ease of use …

Because there are so many possible variations — and because dose accuracy is paramount to the treatment working correctly — Sarepta and Marks developed a final design that makes counting the number of vials as easy as possible for hospital workers.

That turns out to be in groups of five. Makes sense, right? Who remembers learning to count by fives? Five, 10, 15, 20, 25, 30, and so on.

A representative from Marks tells us, “From our ethnographic and usability testing with pharmacists at children’s hospitals, we learned that arranging vials in a grid pattern and keeping them in rows and columns of five made it the easiest and fastest to count.”

Two package formats lay out the vials:

1. In a 5x5 grid for 25 vials per tray (five rows, with five vials in each row, and up to two tiers so the package can accommodate up to 50 vials).

2. In a 5x7 grid for 35 vials per tray (seven rows, with five vials in each row, and two tiers to hold from 51 to 70 vials). This outer box is larger than the one holding vials in the 5x5 grid.

Vials are manually loaded into a standard vial tray that is set up to hold up to 25 vials in a 5x5 grid or 35 vials in the 5x7 configuration. A simple top sheet — customized for each vial configuration — is dropped on top and covers any holes not filled with a vial.

For example, “If less than 25 vials were being used — such as 12 vials in a tray — then a top sheet is added to only expose the 12 compartments in use and conceal the 13 empty compartments,” says the Marks spokesperson. “In addition to making it faster to count, the top sheet also helps the healthcare professionals with ensuring the correct number of vials are there for the patient.”

Sarepta Therapeutics and Marks

Healthcare professionals wear gloves when administering the product; Marks accounted for this with adequate spacing between the vials in the tray. The spacing also minimizes contact to prevent the possibility of breakage.

During development, Marks tested various secondary packaging design concepts with healthcare workers. “Certain packaging design concepts we considered arranged the vials in various ways, such as in a round, tiered arrangement,” says the Marks representative. “While aesthetically pleasing, these were more difficult to accurately count and verify the correct number of vials. Healthcare professionals gave us this feedback in usability testing of the packaging concept prototypes.” 

For the final design, aesthetic influences took a back seat to easy and accurate dosing. “This came down to the arrangement of vials,” says the Marks representative. “We had to ensure the vials were organized in a way that prioritized simplicity — easily scannable for healthcare professionals. Some of our initial protypes were sidelined in favor of this like, as said above, round, tiered arrangements.”

Sarepta prefers not to identify its packaging suppliers, but did tell us that the hinged lid and vial trays are 80-point litho-wrapped chipboard cartons. Vial partitions are 24-point solid-bleached-sulfate (SBS) board.

This carton has an angled hooded lid that requires custom handmade assembly, “beyond what is typically used to automate rigid setup box machines,” says the Marks spokesperson.

Sarepta Therapeutics and Marks

Marks also added a plastic grommet to the trays to help healthcare workers handle the trays. A drawbridge on the front of the outer box also opens up to allow easier removal of the trays.

Despite the ability to accommodate so many different configurations, the secondary packaging design minimizes the number of unique packaging components. Common elements in all 61 configurations include the vial tray, the partitions, the outer box, the tray grommet, the swab envelope, and the tamper-evident seal.

“The top sheet has the most unique configurations,” the Marks representative says, “but it is shipped flat to the CMO to minimize inventory and storage space.”

Like many drugs and treatments these days, Elevidys is shipped and stored at ultra-low temperatures — at -80°C — to maintain stability and integrity. It must be thawed before infusion, either in a refrigerator for up to 14 days or at room temperature in about two hours. Once thawed, the drug must be infused within six hours.

Sarepta explains that there are various checkpoints throughout the manufacturing and distribution process to ensure integrity of the cold chain is maintained. But the packaging helps, too, by being able to withstand extreme temperature fluctuations, from ultra-cold to ambient. How? The packaging uses thick laminated chipboard for the vial trays and the outer box, as well as custom adhesives that withstand temperature fluctuations.

Ultra-cold storage space at hospitals is often limited. Sarepta explains, “Specialty pharmacies and hospitals invested in ultra-cold freezers during the COVID-19 pandemic, which has helped immensely. With additional cell and gene therapies on the horizon, the need for space-efficient packaging is always there.”

Limited freezer space did influence the footprint of this package design. “It was one of the factors in narrowing down the packaging concepts,” admits the Marks spokesperson. “Solutions with a rectilinear footprint maximize space efficiency on freezer shelves, as opposed to a more round, cylindrical shape.”

Neither the primary nor secondary packaging indicates when the product is out of temperature range. But the shipping container with dry ice does monitor the temperature.

According to Sarepta, the kits are labeled and packed for the individual recipient once the order is in. Shipments are dispatched and tracked carefully, with multiple checks along the supply chain, including RFID-enabled labels, to ensure the shipment is sent to the right location and is ready for the correct patient.

Patient information is added to a label on the top of the box.

The two-tier tray is not designed to sit by the patient during infusion. According to the Sarepta website, doses are pulled out of the vials in 60 mL siliconized polypropylene syringes with (preferred) 21-gauge or smaller stainless steel needles. Syringes are then capped and delivered to the patient at room temperature.

The empty packaging must then be properly disposed of to prevent it from being stolen and reused for counterfeiting. “Sites of care are trained on disposal of the empty packaging once the infusion has occurred to avoid this,” says the Sarepta spokesperson. “We have not had any issues with counterfeiting of Elevidys thus far, but it’s important to remain vigilant in that regard, which is why we take steps to ensure product integrity throughout the process and ensure all shipments are monitored and tracked.”

Like many pharmaceuticals, Elevidys incorporates multiple security features built into the packaging to prevent counterfeiting. But the company does not reveal these publicly.

Sarepta declined to say what the volume for Elevidys might be annually. I specifically asked because the packaging is hand-assembled and manually packed. But Sarepta confirms that manual operations can keep up with production demands.

When asked who the CMO and packaging suppliers were, Sarepta said they work with a number of partners but opted not to identify them.

The packaging supplier hand assembles the packaging and sends it to the CMO.

Marks explains, “The outer box design has an angled hooded lid design that requires custom handmade assembly, beyond what is typically used to automate rigid setup box machines.”

Once an order is received, Sarepta’s CMO labels the vials and prepares each kit by putting the appropriate number of vials for the order. Sarepta says, “They are a key partner and their feedback [is] an important part of the process.”

As mentioned earlier, the CMO was involved during packaging development to make sure the packing process was streamlined. “Numerous rounds of iterative prototyping of physical samples were made throughout the project to explore, learn, develop, and refine the concepts,” says the spokesperson from Marks. “Throughout the project, a combination of physical prototypes and digital concepts were used as part of the design and development process.”

The custom top sheet, as well as the rule of five, also aids assembly at the CMO. Sarepta explains that Elevidys is brought to around -20-degrees for vial labeling and kitting. “Employees wear appropriate protective gear while working in those temperatures — parkas and such — all of which is specified in the protocols.”

A vision system confirms that the correct number of vials are in each kit prior to final boxing and shipping.

Elevidys is available for commercial sales in the US, with Roche handling commercialization outside the US. In June 2024, Roche applied for approval in Europe. The drug is also approved in several Middle Eastern countries.

Trials are ongoing, too, though. For example, Sarepta is in a global Phase 3 trial for older boys, including those who are no longer able to walk. The company also has long-term follow-ups and additional studies for those with pre-existing antibodies.

In the fight against Duchenne muscular dystrophy, Sarepta’s Elevidys gene therapy represents a remarkable step forward, providing hope to families and patients by slowing the disease’s devastating progression.

The meticulous precision in dosing and packaging — from the rule-of-five vial arrangements to ultra-cold chain considerations — underscores the collaborative effort behind this life-saving therapy. By prioritizing ease of use, safety, and efficiency, Sarepta ensures that Elevidys reaches patients reliably and securely.

• A rare genetic disease, Duchenne primarily affects males, occurring in about 1 in 3,500 to 5,000 male births worldwide. DMD rarely affects females. Around 9,000 to 12,000 people in the US and around 250,000 to 300,000 people globally live with DMD.

• Muscle degeneration begins before birth. Children with DMD unknowingly experience irreversible muscle damage before receiving a diagnosis.

• The average age of diagnosis is 5 years old.

• However, the first signs of Duchenne may appear as early as 2 to 3 months of age. Muscle weakness becomes increasingly noticeable between the ages of 3 and 5 years. Most children living with DMD use a wheelchair by 13 years old.

• Duchenne has no cure. The leading causes of death from DMD are respiratory or cardiac failure, which typically occurs when patients are in their mid-20s/early 30s.